Letter pubs.acs.org/OrgLett
Thermolysis of Geminal Diazides: Reagent-Free Synthesis of 3‑Hydroxypyridines Hellmuth Erhardt, Kevin A. Kunz, and Stefan F. Kirsch* Organic Chemistry, Bergische Universität Wuppertal, Gaußstraße 20, 42119 Wuppertal, Germany S Supporting Information *
ABSTRACT: An operationally simple protocol for the rapid and efficient construction of highly substituted 3-hydroxypyridines is presented. The thermally induced cyclization of easily constructed geminal diazides derived from βketoesters having an additional olefin moiety affords the title compounds in yields up to 97% under reagent-free conditions. The new method allows for the synthesis of preparative quantities of material. Additionally, the synthetic utility of the pyridine products for the synthesis of valuable heterocycles is described.
T
he intriguing chemical nature of the pyridine heterocycle in combination with its prominence in natural products1 and pharmaceuticals2 has inspired chemists to develop new and efficient methodologies toward its synthesis.3 In particular, 3hydroxypyridines have recently attracted attention due to their promising biological activity (Figure 1). The motif can be
Scheme 1. Strategies for the Synthesis of 3-Hydroxypyridines
Figure 1. 3-Hydroxyypridines in nature and medicinal chemistry.
of dihydropyridines through highly regioselective hetero-Diels− Alder cycloaddition followed by aromatization to the 3hydroxypyridine core.13 We came in contact with this field of heterocyclic chemistry as part of our ongoing efforts to employ geminal diazides as valuable synthetic intermediates.14 More recently, we have reported methods for the synthesis of geminal triazides15a and geminal diazides derived from 1,3-dicarbonyls.16 We also used geminal diazides for the synthesis of azidomethylenebistriazoles and their corresponding geminal tristriazoles.17 The thermolysis of geminal diazides became of particular interest: Early studies hinted at a great, but still undisclosed, potential for the synthesis of nitrogen-containing heterocycles.18 By expansion of the works by Rank and Ogilvie,18c we showed that geminal diazides are powerful starting materials for the preparation of 1,3,4-oxadiazoles through thermolysis, as exemplified in eq 1.19 To our surprise, conventional heating of geminal diazide 1a with an additional olefin moiety in xylene did not provide the
found in nosiheptide4 and nocathiacine,5 both of which exhibit antibiotic activity and are valuable entries to the family of thiopeptide antibiotics. The 3-hydroxypyridine core is also part of caerulomycin B6 isolated from Streptomyces caeruleus and persynthamide.7 Arguably the most known representative is vitamin B6, an essential cofactor of the amino acid metabolism.8 3-Hydroxypyridines are also valuable starting materials for the synthesis of furopyridines, many of which are promising B-Raf inhibitors.9 Several methods for the synthesis of 3-hydroxypyridines have been developed,10 some of which are depicted in Scheme 1. In particular, questions regarding the regioselective construction of this heterocyclic core are still an ongoing important synthetic challenge. For example, Renard and co-workers contributed to this area via Kondrat’eva cycloaddition and subsequent cleavage of the resulting oxabicyclic products.11 Yanagisawa and coworkers utilized ring-closing metathesis for the construction of pyridinones, which afforded 3-hydroxypyridines upon oxidation.12 Moreover, Arndt and co-workers achieved the synthesis © XXXX American Chemical Society
Received: November 21, 2016
A
DOI: 10.1021/acs.orglett.6b03475 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
temperature. In addition, microwave irradiation resulted in a marked decrease of decomposition, as judged from TLC controls. We also note that unspecific intermolecular side reactions may cause lowered yields at concentrations above 0.1 M;20 however, highly diluted reaction mixtures (
